Stroke is presently recognized as the third leading cause of adult disability and death in the United States and Europe. In the past decade, several therapeutic approaches for the minimization of stroke-related brain damage have been pursued including inhibitors of AMPA/kainate, N-methyl-D-aspartate (NMDA) and adenosine reuptake inhibitors. It is the object of the present invention to provide novel compounds that will modulate potassium channels, in particular, large-conductance calcium-activated potassium (BK) channels which will be useful in reducing neuronal damage during ischemic conditions of a stroke episode.
Potassium channels play a key role in regulation of cell membrane potential and modulation of cell excitability. Potassium channels are themselves regulated by voltage, cell metabolism, calcium ion and receptor mediated processes. [Cook, N. S., Trends in Pharmacol. Sciences, 9, pp. 21–28 (1988); and Quast, U. and Cook, N. S., Trends in Pharmacol. Sciences, 10, pp. 431–435 (1989)]. Calcium-activated potassium (KCa) channels are a diverse group of ion channels that share a dependence on intracellular calcium ions for activity. The activity of KCa channels is regulated by intracellular [Ca2+], membrane potential and phosphorylation. On the basis of their single-channel conductances in symmetrical K+ solutions, KCa channels are divided into three subclasses: large conductance (BK) >150 pS; intermediate conductance 50–150 pS; small conductance <50 pS. (“pS” stands for picosiemen, a unit of electrical conductance.) Large-conductance calcium-activated potassium (BK) channels are present in many excitable cells including neurons, cardiac cells and various types of smooth muscle cells. [Singer, J. J. and Walsh, J. V., Pflügers Archiv., 408, pp. 98–111 (1987); Baró, I., and Escande, D., Pflügers Archiv., 414 (Suppl. 1), pp. S 168–S 170 (1989); and Ahmed, F. et al., Br. J. Pharmacol., 83, pp. 227–233 (1984)].
Potassium ions play a dominant role in controlling the resting membrane potential in most excitable cells and in maintaining the transmembrane voltage near the K+ equilibrium potential (Ek) of about −90 mV. It has been shown that opening of potassium channels shifts the cell membrane potential towards the equilibrium potassium membrane potential (Ek), resulting in hyperpolarization of the cell. [Cook, N. S., Trends in Pharmacol. Sciences, 9, pp. 21–28 (1988]. Hyperpolarized cells show a reduced response to potentially damaging depolarizing stimuli. BK channels which are regulated by both voltage and intracellular Ca2+ act to limit depolarization and calcium entry and may be particularly effective in blocking damaging stimuli. Therefore cell hyperpolarization via opening of BK channels may result in protection of neuronal cells under ischemic conditions.
The role of potassium channels in the operation of the smooth muscle of the human urinary bladder is discussed by S. Trivedi, et al. in Biochemical and Biophysical Research Communications, (1995), 213, No. 2, pp. 404–409.
A range of synthetic and naturally occurring compounds with BK opening activity have been reported. The avena pyrone extracted from avena sativa-common oats has been identified as a BK channel opener using a lipid bi-layer technique [International Patent application WO 93/08800, published May 13, 1993]. The flavanoid, Phloretin has been found to affect the opening of Ca2+-activated potassium channels in myelinated nerve fibers of Xenopus laevis using outside-out patches [Koh, D-S., et al., Neuroscience Lett., 165, pp. 167–170 (1994)].
Varia disclosed the use of phosphonomethoxy derivatives as prodrugs of the hydantoin Phenytoin in J. Pharm. Sci. 73, pp. 1068–1073 (1984). In the same publication, they have also disclosed the use of 3-(hydroxymethyl) sulfate of Phenytoin as a potential hydantoin prodrug.

Bungaard, et al. have shown in WO 9008128 and in J. Med. Chem. 32, pp. 2503–2507 (1989) that drugs such as the hydantoin Phenytoin can be derivatized as N-[[[(Aminomethyl)benzoyl]oxy]methyl] derivatives and that the N-[[[(Aminomethyl)benzoyl]oxy]methyl] functionality is cleaved in human plasma to afford the parent hydantoin.

Hewawasam, et al. demonstrated in U.S. Pat. No. 5,602,169 issued Feb. 11, 1997, that (S)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)indolin-2-one is a modulator of large-conductance, calcium-activated potassium (BK) channels, and is useful for the treatment of ischemia.
Hewawasam et. al. in U.S. Pat. No. 5,602,169 also described the synthesis of the above compound and its utility to treat disorders sensitive to potassium channel opening, including cerebral ischemia and traumatic brain injury. Due to the low aqueous solubility of the above compound, additives such as dimethylsulfoxide and propylene glycol, for example, must be employed in order to prepare solutions of the compound of Formula I suitable for intravenous injection (Gribkoff, et al., Nature Medicine, 2001, 7, 471–477).